Salmonella enterica serovar Typhi (S. Typhi) and the related serovar S. Paratyphi cause typhoid fever in humans, a devastating disease that results in ~500,000 deaths every year. Although most of the cases occur in developing countries, outbreaks occasionally occur in the United States. Unlike other Salmonella enterica serovars, which can infect a variety of hosts and can cause limited gastroenteritis (e. g. food poisoning), S. Typhi and S. Paratyphi are exclusive human pathogen and causes systemic, often lethal, disease. Despite being one of the earliest recognized pathogens in human history, the pathogenesis of S. Typhi still remains poorly understood. The molecular bases for S. Typhi's remarkable host specificity are also poorly understood. Genome sequence data suggest that a combination of genome degradation and acquisition of unique genetic information may account for S. Typhi's unique biology. One of the very few virulence factors that are unique to typhoidal serovars of S. enterica is Typhoid toxin, which was recently discovered in our laboratory. Typhoid toxin is an atypical AB toxin in that it has two enzymatically active subunits: an ADP ribosyl transferase (PltA) and a deoxyribonuclease (CdtB), which are homologs of the active subunits of pertussis and cytolethal distending toxins, respectively. These two subunits are covalently linked to one another and are associated to a homopentameric B subunit composed of PltB. We have recently discovered that systemic administration of purified typhoid toxin can recapitulate many of the symptoms of typhoid fever in mice. This is a very exciting discovery since it not only links typhoid toxin to the pathogenesis of typhoid fever but also provides concrete bases for the development of novel prevention as well as potentially life-saving therapeutic strategies. Typhoid toxin exhibits a remarkable biology in that it is only produced by intracellularly located bacteria, and after its synthesis and assembly, it is released into the Salmonella-containing vacuole. From this location, the toxin is then packaged into vesicle carriers and exported to the extracellular medium, from where it finds its way into target cells by interacting with specific surface receptors. Our laboratory has recently identified the surface receptors for typhoid toxin, which revealed unique insights into the biology of this toxin. In addition, we have discovered that a Rab32 and BLOC-3-dependent pathogen surveillance mechanism restricts the growth of S. Typhi in mice. We intend to leverage these exciting findings to carry out a series of research objectives that, through the study of typhoid toxin, we hope will deepen our understanding of typhoid fever and the pathogenesis of S. Typhi infection.